Approaches and Model Systems

From a technical standpoint, we employ a variety of approaches, some of which are multidisciplinary and/or were developed in our lab. These include 3D electron microscopic analysis, in vitro and in vivo single and multi-cell targeted recordings, whole-brain connectivity mapping of recorded cells, optogenetics, modelling and behaviour. Our lab works almost exclusively on mice, which offer a tractable experimental system for establishing causal relationships between the functional connectivity of mammalian neuronal circuits and behaviour.


The cortex

In mammals, a six layered cortex evolved into what is considered by many to be the most complicated machine in biology. Pioneering mapping studies in the early 20th century by Penfield, Woolsey, Mountcastle and colleagues revealed that this intimidating structure consists of functionally discrete areas representing, for example, parts of the body or a particular sensory modality.  During this classical period, electrophysiological experiments were also revealing that the sensory response properties of cortical neurons are often, though not always, more complex that those observed in the periphery and subcortical nuclei. Today, it is widely accepted that, in a given local area at the fine-scale cellular level, there remains immense diversity in the sensory response properties of neurons both within and across cortical layers. What remains one of the most challenging tasks in systems neuroscience is to understand the wiring principles of these circuits and how such connectivity rules permit such diverse functionality.

One hypothesis is that sensory cortical function reflects a hierarchical network of connectivity (based on seminal work of David Hubel and Torsten Wiesel)

One hypothesis is that sensory cortical function reflects a hierarchical network of connectivity (based on seminal work of David Hubel and Torsten Wiesel)

In order to understand the functional connectivity of cortical circuits, our lab uses the primary visual cortex (and its intercortical connectivity) as a model system to interrogate stimulus response diversity. The sources of such heterogeneity include the identity and function of both local and long-range presynaptic input onto different cell types and their demonstrated range of integrative properties. Currently we are focusing on the principal cells in cortical layers 2/3 and 6 that are known to exhibit variable tuning to stimulus orientation, direction and velocity. Recently we showed that two morphologically distinct populations of neurons in layer 6 have unique biophysical profiles and are differentially tuned to visual stimuli. In contrast to poorly tuned cortico-cortical (CC) cells, cortico-thalamic (CT) projecting cells are reliably highly tuned to stimulus orientation and innervated by distinct cortical cell populations. This raises the possibility that distinct cell types route specific types of information within and out of this functionally complex cortical circuit.

 
 

The olfactory bulb

The glomerular circuit of the olfactory bulb is another model system of choice because local circuits can be identified and genetically targeted from one mouse to the next, is anatomically relatively simple and its cellular composition is well understood.  At the level of the bulb, some 1800 glomeruli are involved in the first relay of the olfactory signal whereby principal cells (PNs) receive excitatory input from a functionally specific subset of sensory inputs projecting exclusively to one or two glomeruli. Via active odour sampling and recurrent and lateral inhibition, odour-specific temporal patterns of action potential activity in PNs are rapidly generated and transmitted for readout in downstream olfactory cortex. 

Olfactory glomerular circuits (Golgi, 1875)

Olfactory glomerular circuits (Golgi, 1875)

Our lab discovered that the very significant intrinsic biophysical diversity found across the same morphological class of PNs reflects a biophysical signature of glomerulus network-specific processing of odour information. This suggests that the history, and potentially the context, of glomerulus activity can directly regulate and continually modulate the properties of neurons in the circuit. At present we are investigating whether similar homotypic regulatory mechanisms apply to glomerular inhibitory networks, and precisely how and why glomerular circuits regulate neuronal excitability in this way.